Feature Finding Figure
Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may be associated with robust molecular changes in female subjects, and investigated large-scale gene expression in the post mortem brains of MDD subjects and matched controls. We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation (Figure, panels b and c). Among the most robust findings were downregulated transcripts for genes coding for GABA interneuron related peptides, including somatostatin (SST) (Figure), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic or clinical measures. BDNF itself was significantly downregulated at the mRNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile is recapitulated by complementary patterns in mice with constitutive BDNF or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low mRNA/protein) and indirect (low BDNF-dependent gene expression pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.
Guilloux J-P, Douillard-Guilloux G, Kota R, Wang X, Gardier A, Martinowich K, Tseng GC, Lewis DA, Sibille E: Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry, ePub September 13, 2011.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
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